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Jami, Eshim S.; Hammerschlag, Anke R.; Ip, Hill F.; Allegrini, Andrea G.; Benyamin, Beben; Border, Richard; Diemer, Elizabeth W.; Jiang, Chang; Karhunen, Ville; Lu, Yi; Lu, Qing; Mallard, Travis T.; Mishra, Pashupati P.; Nolte, Ilja M.; Palviainen, Teemu; Peterson, Roseann E.; Sallis, Hannah M.; Shabalin, Andrey A.; Tate, Ashley E.; Thiering, Elisabeth; Vilor-Tejedor, Natalia; Wang, Carol; Zhou, Ang; Adkins, Daniel E.; Alemany, Silvia; Ask, Helga; Chen, Qi; Corley, Robin P.; Ehli, Erik A.; Evans, Luke M.; Havdahl, Alexandra; Hagenbeek, Fiona A.; Hakulinen, Christian; Henders, Anjali K.; Hottenga, Jouke Jan; Korhonen, Tellervo; Mamun, Abdullah; Marrington, Shelby; Neumann, Alexander; Rimfeld, Kaili; Rivadeneira, Fernando; Silberg, Judy L.; Beijsterveldt, Catharina E. van; Vuoksimaa, Eero; Whipp, Alyce M.; Tong, Xiaoran; Andreassen, Ole A.; Boomsma, Dorret; Brown, Sandra A.; Burt, S. Alexandra; Copeland, William; Dick, Danielle M.; Harden, K. Paige; Harris, Kathleen Mullan; Hartman, Catharina A.; Heinrich, Joachim; Hewitt, John K.; Hopfer, Christian; Hypponen, Elina; Jarvelin, Marjo-Riitta; Kaprio, Jaakko; Keltikangas-Jarvinen, Liisa; Klump, Kelly L.; Krauter, Kenneth; Kuja-Halkola, Ralf; Larsson, Henrik; Lehtimaki, Terho; Lichtenstein, Paul; Lundstrom, Sebastian; Maes, Hermine H.; Magnus, Per; Munafo, Marcus R.; Najman, Jake M.; Njolstad, Pal R.; Oldehinkel, Albertine J.; Pennell, Craig E.; Plomin, Robert; Reichborn-Kjennerud, Ted; Reynolds, Chandra; Rose, Richard J.; Smolen, Andrew; Snieder, Harold; Stallings, Michael; Standl, Marie; Sunyer, Jordi; Tiemeier, Henning; Wadsworth, Sally J.; Wall, Tamara L.; Whitehouse, Andrew J. O.; Williams, Gail M.; Ystrom, Eivind; Nivard, Michel G.; Bartels, Meike and Middeldorp, Christel M. (2022): Genome-wide Association Meta-analysis of Childhood and Adolescent Internalizing Symptoms. In: Journal of the American Academy of Child and Adolescent Psychiatry, Vol. 61, No. 7: pp. 934-945

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Objective: To investigate the genetic architecture of internalizing symptoms in childhood and adolescence. Method: In 22 cohorts, multiple univariate genome-wide association studies (GWASs) were performed using repeated assessments of internalizing symptoms, in a total of 64,561 children and adolescents between 3 and 18 years of age. Results were aggregated in meta-analyses that accounted for sample overlap, first using all available data, and then using subsets of measurements grouped by rater, age, and instrument. Results: The meta-analysis of overall internalizing symptoms (INToverall) detected no genome-wide significant hits and showed low single nucleotide polymorphism (SNP) heritability (1.66%, 95% CI = 0.84-2.48%, n(effective) = 132,260). Stratified analyses indicated rater-based heterogeneity in genetic effects, with self-reported internalizing symptoms showing the highest heritability (5.63%, 95% CI = 3.08%-8.18%). The contribution of additive genetic effects on internalizing symptoms appeared to be stable over age, with overlapping estimates of SNP heritability from early childhood to adolescence. Genetic correlations were observed with adult anxiety, depression, and the well-being spectrum (vertical bar r(g)vertical bar > 0.70), as well as with insomnia, loneliness, attention-deficit/hyperactivity disorder, autism, and childhood aggression (range vertical bar r(g)vertical bar = 0.42-0.60), whereas there were no robust associations with schizophrenia, bipolar disorder, obsessive-compulsive disorder, or anorexia nervosa. Conclusion: Genetic correlations indicate that childhood and adolescent internalizing symptoms share substantial genetic vulnerabilities with adult internalizing disorders and other childhood psychiatric traits, which could partially explain both the persistence of internalizing symptoms over time and the high comorbidity among childhood psychiatric traits. Reducing phenotypic heterogeneity in childhood samples will be key in paving the way to future GWAS success.

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